Angewandte
Communications
Chemie
Heterocycles
Transition-Metal-Free Regioselective Alkylation of Pyridine N-Oxides
Using 1,1-Diborylalkanes as Alkylating Reagents
Woohyun Jo+, Junghoon Kim+, Seoyoung Choi, and Seung Hwan Cho*
Dedicated to Professor Kyo Han Ahn on the occasion of his 60th birthday
Abstract: Reported herein is an unprecedented base-promoted
deborylative alkylation of pyridine N-oxides using 1,1-diboryl-
alkanes as alkyl sources. The reaction proceeds efficiently for
a wide range of pyridine N-oxides and 1,1-diborylalkanes with
excellent regioselectivity. The utility of the developed method is
À
demonstrated by the sequential C H arylation and methylation
of pyridine N-oxides. The reaction also can be applied for the
direct introduction of a methyl group to 9-O-methylquinine N-
oxide, thus it can serve as a powerful method for late-stage
functionalization.
T
he direct alkylation of pyridines has emerged as an
expedient and atom-economical strategy[1] for the prepara-
tion of alkylated pyridines which form the core structures of
many biologically active compounds, pharmaceuticals, and
agrochemicals.[2] Consequently, a range of metal-mediated
À
C H alkylation reactions of pyridines have been successfully
developed using late-transition metals[1,3] and lanthanides[4] as
Scheme 1. Strategies for the alkylation of pyridines or pyridine
N-oxides. pin=pinacol.
À
catalysts (Scheme 1a). The radical C H alkylation of pyr-
idines in the presence of photocatalysts, metal catalysts, or
stoichiometric amounts of oxidants has also been extensively
studied in this area of research (Scheme 1b).[5] However,
concerns regarding high costs and the presence of residual
metal impurities often make these approaches unsuitable for
industrial and pharmaceutical applications. Moreover, the
radical approach has often resulted in the formation of an
inseparable mixture of regioisomers. Thus, the development
of an efficient and selective method for the alkylation,
especially for the methylation,[3d,6,7] of pyridines under
transition-metal-free conditions is still desirable.
The reaction of pyridine N-oxides with certain nucleo-
philes through a nucleophilic addition/elimination mechanism
is a well-known approach for the preparation of functional-
ized pyridine compounds.[8] Although numerous methods for
the introduction of functional groups such as halides, cyano,
amino, phenoxy, thioalkyl, and phosphoryl into pyridine N-
oxides have been developed,[8,9] only a limited number of
pyridine N-oxides have not been well documented.[11] In
2000, Nicolaou et al. described C2-methylation reactions of
pyridine N-oxides using Tebbeꢀs reagent involving a nucleo-
philic addition/elimination process.[11a] Almqvist, Olsson,[11b,c]
and Duan[11d] discovered that Grignard reagents act as facile
nucleophiles in the C2 alkylation of pyridine N-oxides.
Herein, we report the development of the transition-metal-
free alkylation of pyridine N-oxides by employing 1,1-
diborylalkanes as facile alkylating reagents (Scheme 1c).
This new process is operationally simple and works with
a range of pyridine N-oxides and 1,1-diborylalkanes.
Recently, we[12] and others[13] have reported that 1,1-
diborylalkanes can be utilized in various organic transforma-
tions under metal-catalyzed or transition-metal-free condi-
tions. Among the reported reactions, Morken et al. described
that a-borylcarbanion intermediates, generated in situ from
the reaction of 1,1-diborylalkanes with an alkoxide base,
could facilitate a formal SN2-type alkylation with alkyl
halides.[13f,g] In light of these precedents, we wondered
whether the a-borylcarbanion could react with pyridine N-
oxides in a nucleophilc aromatic substitution fashion. To test
the feasibility of the idea, we initially focused on the reaction
of quinoline N-oxide (1a) with diborylmethane (2a) in the
presence potassium tert-butoxide in toluene at 808C
(Table 1). To our surprise, the deoxygenated 2-methylquino-
line (3a) was obtained as a single product, albeit in moderate
yield (entry 1). Subsequent base screening (entries 2–7)
À
examples for the C C bond-forming reactions have been
reported.[10] Specifically, the regioselective alkylation of
[*] W. Jo,[+] J. Kim,[+] S. Choi, Prof. Dr. S. H. Cho
Department of Chemistry and Division of Advanced Nuclear
Engineering, Pohang University of Science and Technology (POST-
ECH), Pohang, 790-784 (Rep. of Korea)
E-mail: seunghwan@postech.ac.kr
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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